Implant device with a retinoid for improved biocompatibility

ABSTRACT

An implant device is provided which incorporates a retinoid for improving the biocompatibility of the device in tissue. The device may be bioerodible for the purpose of systemically or locally releasing a therapeutic agent in tissue or it may be a permanent implant which includes a surface treated with a retinoid for increasing the biocompatibility thereof.

[0001] The present application is a continuation-in-part of U.S. Ser.No. 09/356,074 filed Jul. 16, 1999, now U.S. Pat. No. which is acontinuation of U.S. Ser. No. 09/150,990 filed Sep. 10, 1998, nowabandoned which is a continuation of U.S. Ser. No. 08/908,094 filed Aug.11, 1997, now abandoned.

[0002] The present invention is generally related to implantable devicesand is more particularly directed to an implantable prosthesis havingimproved biocompatibility. Still more particularly, the presentinvention is directed to an implantable device having improvedbiocompatibility while providing systemic release of a therapeutic agentin tissue.

[0003] It should be appreciated that physiological compatibility andbiocompatibility are common problems for both implants for providing asystemic, or local, release of the therapeutic agent and for prosthesis,i.e., implants, utilized for functional or cosmetic reasons, or both.

[0004] It should be appreciated that the term “biocompatible” in thepresent application relates to a foreign object that can be left in ahuman or animal body for an extended or an indefinite period withoutcausing any adverse physiological action.

[0005] The functional biocompatibility of an implant or device, is, ofcourse, determined by the chemical and surface properties of the implantand its components. The general structure of a device, includingmechanical strength, elasticity, flexibility, fatigue resistance,chemical inertness, impermeability to water, resistance to acid, etc.,all contribute to biocompatibility which, of course, also depends uponthe type of tissue into which the implant is to be inserted. Mostimportantly, the surface of the implant in contact with body tissuesshould also exhibit resistance to immunological attack, cell adhesion,pannus formation, etc.

[0006] Undesirable properties which can result from tissue interactingwith the surface may significantly affect the efficiency of the implantand be counteractive to the intended use of the implant in certainmedical devices, for example, sustained or controlled drug releasedevices.

[0007] The use of a sustained, or controlled release system has a wellknown advantage of providing an active agent at a relatively constantlevel of concentration in tissue. Sustained drug release systems havebeen utilized in a great number of applications including drug releaseinto the vitreous for endophthalmitis and other vitreoretinal disorderswith the use of antibiotics and a fungal agent, antineoplastic drugs andanti-inflammatory agents.

[0008] Unfortunately, in many instances, particularly where the implantis intended to remain in contact with tissue for extended periods oftime, various problems associated with the physiological and chemicalstability and compatibility with respect to various of the contactedtissues and biological fluids occurs. This is true even though theimplant may function properly in its sustained or controlled release ofthe active agent.

[0009] For example, biomaterial such as a synthetic polymer, whencontacted with blood, rapidly forms an adsorbed protein layer.Subsequently, conformational alterations and complexing of proteinswhich may occur which activate defense mechanisms such as coagulation,platelet adhesion, and aggregation, white cell adhesion, etc.

[0010] In eye tissue, an implant may cause superficial vascularizationof the cornea with infiltration of granulation tissue. Biodegradablepolymers may cause mild foreign body reactions which includeinflammation in the vitreous.

[0011] Implanted biomaterials will cause a typical foreign body reactionwith fibrinous membrane formation. A fibrinous membrane will surroundand encapsulate the implant. Contraction of this fibrous capsule canrange from transient pain to serious sequelae depending upon thelocation. Fibrinous infiltration of the vitreous with a prominentinflammatory response can lead to traction retinal detachment,disruption of the retinal pigmented epithelium or breakdown of the bloodretinal barrier. Tissue and organ adhesions may develop as a result ofthe fibrinous inflammation. Intraocular implants can also cause cataractformation. Irisciliary body adhesions would seriously effect thehomeostasis of ocular tension. Implants, being foreign objects, maycause acute and chronic inflammation. Tissue necrosis and scarring mayresult as well as neovascularization. Biopolymers may often be antigenicand elicit allergic or other adverse events. In the case of animplantable material in the vasculature or heart thrombus formation andembolus may occur.

SUMMARY OF THE INVENTION

[0012] In accordance with one embodiment of the present invention, animplantable device is provided for systemic, or local, release of atherapeutic agent in tissue. The device generally includes a therapeuticagent along with a carrier sized for insertion into tissue in which thesystemic release of a therapeutic agent is desired, the carrierincluding means for providing sustained or controlled release of thetherapeutic agent.

[0013] In addition, retinoid means, present in the carrier, is providedfor improving biocompatibility of the device in the tissue.

[0014] As will be described in detail hereinafter, this hereinbeforeunrecognized property of a retinoid substantially reduces or preventsundesirable attributes which can result from tissue interacting with thesurface of the implantable device.

[0015] More particularly, in accordance with the present invention, theretinoid means may comprise a retinoid receptor agonist and thetherapeutic agent, carrier, and retinoid means, may be homogeneous. Thishomogeneity provides for ease of manufacturing through the use of simpleextrusion techniques or injection molding.

[0016] Specifically, in accordance with this embodiment of the presentinvention, the means for providing time release of the therapeutic agentmay comprise a biodegradable polymer, such as, for example, apoly(lactic acid) and poly(lactide-co-glycolide).

[0017] More particularly, in accordance with one embodiment of thepresent invention, the carrier may be sized for implanting into a scleraand the retinoid receptor agonist may be a retinoid acid, for example,selected from the group of naturally occurring retinoids such as VitaminA (retinol), Vitamin A aldehyde (retinal), Vitamin A acid (retinoicacid) and their synthetic and natural congeners. These would include butnot be limited to the isomers all trans; 9-cis; 11-cis; 13-cis;9,11-dicis, and 11,13-dicis as well as physiologically compatibleethers, esters, amides and salts thereof. The 7,8-dihydro and5,6-dihydro congeners as well as etretinate are also acceptable for theinvention.

[0018] Compounds that intrinsically or upon metabolism possess thephysiologic properties of retinoids are also included within the scopeof this invention. These would include synthetic and natural retinoidcompounds having affinity to nuclear retinoic acid receptors (RARs) andretinoid X receptors (RXRs).

[0019] More particularly, the retinoid receptor agonist may beethyl-6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, or6-[2-(4,4-dimethylchroman-6-yl)ethyfyl]nicotinic acid, orp-[(E)-2-(5,6,7,8-tetrahydro-,5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoicacid.

[0020] Corresponding to the device of the present invention, a method inaccordance with the present invention for improving biocompatibility ofan implant in tissue generally includes the steps of providing atherapeutic agent, providing a carrier sized for insertion into tissuein which release of the therapeutic agent is desired, incorporating atherapeutic agent into a carrier in a manner enabling sustained orcontrolled release of the therapeutic agent and incorporating a retinoidinto the carrier in an amount effective for improving biocompatibilityof the carrier in the tissue.

[0021] Many conditions and diseases are treatable with stents,catheters, cannulae and other devices inserted into the esophagus,trachea, colon, biliary tract, urinary tract and other locations in thebody, or with orthopedic devices, implants, or replacements. It would bedesirable to develop devices and methods for reliably deliveringsuitable agents, drugs or bioactive materials directly into a bodyportion during or following a medical procedure, so as to treat orprevent such conditions and diseases, for example, to prevent abruptclosure and/or restenosis of a body portion such as a passage, lumen orblood vessel.

[0022] As a particular example, it would be desirable to have devicesand methods which can deliver an antithrombic or other medication to theregion of a blood vessel which has been treated by PTA, or by anotherinterventional technique such as atherectomy, laser abllation, or thelike. It would also be desirable that such devices would deliver theiragents over both the short term (that is, the initial hours and daysafter treatment) and the long term (the weeks and months aftertreatment). It would also be desirable to provide precise control overthe delivery rate fro the agents, drugs or bioactive materials, and tolimit systemic exposure to them. This would be particularly advantageousin therapies involving the delivery of a chemotherapeutic agent to aparticular organ or site through an intravenous catheter (which itselfhas the advantage of reducing the amount of agent needed for successfultreatment), by preventing stenosis both along the catheter and at thecatheter tip. A wide variety of other therapies could be similarlyimproved.

[0023] Another embodiment of the present invention includes animplantable device, specifically a surgically implantable prosthesis incombination with retinoid means for improving the biocompatibility ofthe prosthesis. More specifically, the retinoid means may be present inthe form of a film on the prosthesis or, alternatively, bonded to asurface of the prosthesis.

[0024] Other implants to be considered as part of the present inventioninclude biocompatible stents such as described in U.S. Pat. No.5,342,348and 5,554,381, biocompatible bone pins such as described inU.S. Pat. No. 4,851,005, biodegradable/biodegradable joint prosthesissuch as described in U.S. Pat. No. 6,007,580, biodegradable birthcontrol devices such as described in U.S. Pat. No. 5,733,565,biodegradable implants for treatment of prostate cancer or anybiodegradable drug delivery system.

[0025] All of the hereinabove referenced patents are to be incorporatedherewith, including all drawings and specifications, by this specificreferences thereto.

[0026] As hereinabove noted, the retinoid means may comprise a retinoidselected from the group of naturally occurring retinoids such as VitaminA (retinol), Vitamin A aldehyde (retinal), Vitamin A acid (retinoicacid) and their synthetic and natural congeners. These would include butnot be limited to the isomers all trans; 9-cis; 11-cis; 13-cis;9,11-dicis, and 11,13-dicis as well as physiologically compatibleethers, esters, amides and salts thereof. The 7,8-dihydro and5,6-dihydro congeners as well as etretinate are also acceptable for theinvention.

[0027] Compounds that intrinsically or upon metabolism possess thephysiologic properties of retinoids are also included within the scopeof this invention. These would include synthetic and natural retinoidcompounds having affinity to nuclear retinoic acid receptors (RARS) andretinoid X receptors (RXRs).

[0028] Importantly, the present invention encompasses a method forimproving biocompatibility of a surgically implantable prosthesis withthe method comprising the step of combining a retinoid with theprosthesis. More particularly, the step may include disposing a film ofretinoid on the prosthesis or, embedding retinoid, to the surface of theprosthesis. The retinoid may comprise a retinoid, as hereinabove noted,and be selected from the group of naturally occurring retinoids such asVitamin A (retinol), vitamin A aldehyde (retinal), Vitamin A acid(retinoic acid) and their synthetic and natural congeners. These wouldinclude but not be limited to the isomers all trans; 9-cis; 11-cis;13-cis; 9,11-dicis, and 11,13-dicis as well as physiologicallycompatible ethers, esters, amides and salts thereof. The 7,8-dihydro and5,6-dihydro congeners as well as etretinate are also acceptable for theinvention.

[0029] Compounds that intrinsically or upon metabolism possess thephysiologic properties of retinoids are also included within the scopeof this invention. These would include synthetic and natural retinoidcompounds having affinity to nuclear retinoic acid receptors (RARs) andretinoid X receptors (RXRs).

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The advantages and features of the present invention will bebetter understood by the following description when considered inconjunction with the accompanying drawings in which:

[0031]FIG. 1 is an implantable device in accordance with the oneembodiment of the present invention, specifically a retinal plug, forproviding local delivery to the intraocular tissues of a therapeuticagent;

[0032]FIG. 2 is a diagram showing the positioning of the retinal plugshown in FIG. 1 in an eye through the sclera and pars plana;

[0033]FIG. 3 is a perspective view of an alternative embodiment inaccordance with the present invention, specifically a surgicallyimplantable prosthesis such as a zt cardiac valve component coated witha film of retinoid;

[0034]FIG. 4 is a perspective view of a stent coated with a film ofretinoid;

[0035]FIG. 5 is a cross section view of a stud implant coated with afilm of retinoid;

[0036]FIG. 6 in a side view of a joint prosthesis incorporating aretinoid in accordance with the present invention;

[0037]FIG. 7 is a drawing showing the encapsulation of a placebo plug 28days after insertion into the vitreous through sclera. The plug iscomprised of polylactic acid. The plug disappears during the-processingof the eye (A). The tissues surrounding the plug were stained with PASand show a fibrous capsule surrounding the area (B) where the placebowas previously located. The capsule that surrounded the polylactic acidplug shows a very prominent inflammatory response with inflammatory cellinfiltration (C); and

[0038]FIG. 8 is a drawing showing the encapsulation of a retinoidcontaining plug 28 days after insertion. The polylactic acid plugcontained 10% by weight of the retinoid 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinic acid (AGN 190299). The plugdisappears in the processing of the eye (A). The tissues surrounding theretinoid containing plug were stained with PAS. The figure shows thatthe capsule surrounding the AGN190299 plug (B) has very little fibrousinflammation (C).

DETAILED DESCRIPTION

[0039] Turning to FIGS. 1 and 2, there is shown an implantable device 10for providing systemic release of a therapeutic agent in tissue. Device10 is representative of a great number of devices for systemic releaseof a therapeutic agent. This specific embodiment 10 is a sterile,bioerodible plug for the intraocular delivery of pharmaceutically activecompounds. Placement of the device 10 is illustrated in FIG. 2 as it maybe inserted into an eye 12 specifically, the sclera 14 proximate thelens 16 and iris 18 for release of the drug into the sclera, choroid,retina and vitreous cavity. By way of example, the retinal plug, ordevice, 10, may have a weight of about 0.5 to about 10 milligrams, havea diameter of about 0.5 and about 2 millimeters and a length of betweenone and 12 millimeters. A hole 20 through a proximal end 22 of thedevice 10 enables a suture 24 to be used for securing the device 10, asshown in FIG. 2, with a distal end 26 thereof protruding into a vitreouscavity 30.

[0040] Any suitable therapeutic agent may be utilized. The diversity oftherapeutic agents that can be delivered by the present invention isgreat and known to those skilled in the art. Examples include but arenot limited to antibiotics, antifungals and antivirals such aserythromycin, tetracycline, aminoglycosides, cephalosporins, quinolones,penicilins, sulfonamides, ketoconazole, miconazole, acyclovir,ganciclovir, azidothymidine, interferon; anticonvulsants such asphenytoin and valproic acid; antidepressants such as amitriptyline andtrazodone; antiparkinsonism drugs; cardiovascular agents such as calciumchannel blockers, antiarythmics, beta blockers; antineoplastics such ascisplatin and methotrexate, corticosteroids such as dexamethasone,hydrocortisone, prednisolone, and triamcinolone; NSAIDs such asibuprofen, salicylates indomethacin, piroxicam; Hormones such asprogesterone, estrogen, testosterone; growth factors; carbonic anhydraseinhibitors such as acetazolamide; prostaglandins; antiangiogenic agents;neuroprotectants; other drugs known to those skilled in the art tobenefit from controlled or sustained release from implantable devices orcombinations thereof.

[0041] These active agents may be incorporated into a bioerodiblepolymer such as a poly ester, poly (ortho ester), poly (phosphazine),poly (phosphate ester), poly-caprolactone, poly (hydroxybutyric acid),natural polymer such as gelatin or collagen, or a polymeric blend. Inaddition, the present invention may also improve the biocompatibility ofnon-erodible polymeric implants.

[0042] Importantly, a retinoid is incorporated into the device 10 forimproving the biocompatibility thereof. All of the components of thedevice 10 are extruded as a homogeneous system in the shape of a plug.

[0043] The device 10 may be optimized to resist sclera and choroidalerosion in order to prevent disintegration or fragmentation of the plug10 into the vitreous cavity 30. This may be accomplished, as is wellknown in the art, by altering the surface, finish of the plug 10,coating the plug with another biodegradable semipermeable polymer, orthe addition of another polymer to the blend. Because the plug is ahomogeneous system, ease of manufacture is provided through simpleextrusion techniques or injection molding.

[0044] The mechanism and rate of drug release may be controlled by thechoice polymer, polymer molecular weight, polymer crystallinity,copolymer ratios, processing conditions, surface finish, geometry,excipient addition, and polymeric coatings, with the drug being releasedfrom the device 10 by diffusion, erosion, dissolution or osmosis.

[0045] The fabrication of various sclera plugs and the mechanism ofcontrolling the drug release is well known in the art as set forth innumerous publications such as, for example, “Sclera Plug ofBiodegradable Polymers for Controlling Drug Release in Vitreous”,Mototane Hashizoe, Archophthalmol/Volume 112, page 1380-1384, Oct.,1994; “A New Vitreal Drug Delivery Systems Using an ImplantableBiodegradable Polymeric Device”, Hideya Kimura et al, InvestigativeOphthalmology and Visual Science, Volume 35, page 2815-2819, May, 1994,and U.S. Pat. No. 5,466,233, all of which are incorporated herein intheir entirety for the purpose of describing sclera plug manufacture,use and mechanisms.

[0046] All of the active ingredients utilized in the plug device 10 arepresent in a therapeutic effective amount which is calculated to achieveand maintain a therapeutic level in the vitreous cavity and introducedby the vitreous plug. Naturally, the therapeutic amount will vary withthe potency of the active agent, the rate of release by the plug device10.

[0047] The amount of incorporated retinoid will depend on the potencyand receptor selectivity of the retinoid employed as well as the releaserate of the retinoid from the specific implant. Typically, the amount ofretinoid employed represents 0.001% to 50%, more typically from 0.01 to20%

[0048] Retinoic acid receptor agonists have been utilized for preventingproliferation of retinal pigment epithelium, see copending U.S. patentapplication Ser. No. 08/383,741, entitled “Method of PreventingProliferation of Retinal Pigment of Epithelium by Retinoic Acid ReceptorAgonists”, filed in the name of Campochiaro and is to be incorporatedherewith in its entirety for describing the use of retinoic acidactivity in the vitreous cavity 30.

[0049] Importantly, it has been discovered that the use of retinoids canimprove the biocompatibility of the device 10 in tissue. While theretinoid may be incorporated into the device as a component of thehomogeneous mass, as hereinabove described in connection with the plugdevice 10, the retinoid may also be used to advantage for improvingbiocompatibility when disposed as a film 40 on an implanted device 42 asshown in FIG. 3. The device 42 is a component for a cardiac valve as isdescribed in U.S. Pat. No. 5,370,684 which is to be incorporatedherewith in its entirety in describing typical implantable devices 42suitable in combination with the retinoid for improving biocompatibilitythereof. In addition, this patent is to be incorporated herein by thespecific reference thereto for the purpose of coating or embeddingtechniques suitable for bonding the retinoid to the surface 44 of theimplant 42.

[0050] When applied as a film 40 or imbedded into a surface 44 of theimplant 42, the retinoid may be incorporated in amounts depending on thepotency and receptor selectivity of the retinoid employed as well as therelease rate of the retinoid from the specific implant.

[0051] With reference to FIG. 4 there is shown an endovascular stent 80comprising a single helically wound strand 82 and a pair ofcounter-wound filaments 84, 86. Coatings 90,92,96 respectively disposedon the strand 82 and filaments 84, 86 improves the biocompatibility ofthe stent 80 as hereinabove described in connection with the implant 42shown in FIG. 3. Alternatively, the retinoid may be embedded into thestrand 82 and filaments 84, 86.

[0052] The stent 80 may provide delivery of therapeutic and othersubstances to a location within a patients' vascular system. (not shown)

[0053] The endovascular stent comprises a tubular structure having aninitial diameter and being expandable from the initial diameter to anenlarged diameter. The filaments 84, 86, providing a delivery matrix,are interlaced with the tubular structure and expandable therewith fromthe initial diameter to the enlarged diameter. A bioactive substance isreleasably contained within the filament 84, 86 of the delivery matrix,and is released from said matrix when exposed to the conditions presentin the vascular system.

[0054] The tubular structure may be composed of an elastic material,such as an elastomer polymer, whereby the tubular structure may beinitially constrained to set initial diameter and thereafter released tosaid enlarged diameter, Alternatively, the tubular structure could becomposed of a non-plastic material, whereby the tubular structure may beexpanded from the initial diameter to the typically using a balloondilatation catheter.

[0055] The various specific designs for the tubular structure exist,including a helical structure where the filament of the delivery matrixis counter woven with a helical strand of the tubular structure, ahelical structure where the filament is laminated to a helically woundstrand of the tubular structure, and a perforated cylinder where thefilament of the delivery matrixes interwoven through perforations in thecylinder.

[0056] The filaments 84,86 of the delivery matrix may be porous andsubstantially non-erodible, where the bioactive substance is absorbed orimpregnated therein and released over time. Alternatively, the filamentwill be composed of the material which is erodible within the vascularenvironment, where the bioactive substance is contained or dispersed inthe filament and released as the filament material erodes. When anerodible material is used, the retinoid in incorporated therein ashereinabove described.

[0057] With reference to FIG. 5 there is shown in sectional sideelevation, a surgical implant kit 100 including a stud 102 disposedwithin a hole 104 drilled into a bone 106 with a pin 108 driven into apassage 110 through the stud 102. A retinoid coating 114 providesbiocompatibility as hereinabove discussed.

[0058] Turning to FIG. 6, there is shown a joint prosthesis 120including a fibrous spacer 122 held in position between bones 126,128 tobe joined by rigid fixation pins 130,132.

[0059] The spacer 122 may include a biodegradable polymer,co-polymermixture and/or composite such as described in U.S. Pat. No.6,007,580 and including a retinoid as herein described to improvebiocompatibility.

[0060] Typically, the amount of retinoid employed represents 0.001% to50%, more typically from 0.01 to 20%.

[0061] The retinoid may be either naturally occurring or a syntheticretinoid such as a retinoic acid receptor (RAR) agonist.

[0062] Naturally occurring retinoids suitable for use in the presentinvention includes naturally occurring retinoids such as Vitamin A(retinol), Vitamin A aldehyde (retinal), Vitamin A acid (retinoic acid)and their synthetic and natural congeners. These would include but notbe limited to the isomers all trans; 9-cis; 11-cis; 13-cis; 9,11-dicis,and 11,13-dicis as well as physiologically compatible ethers, esters,amides and salts thereof. the 7,8-dihydro and 5,6-dihydro congeners aswell as etretinate are also acceptable for the invention.

[0063] Compounds that intrinsically or upon metabolism possess thephysiologic properties of retinoids are also included within the scopeof this invention. These would include synthetic and natural retinoidcompounds having affinity to nuclear retinoic acid receptors (RARs) andretinoid X receptors (RXRs).

[0064] Other synthetically prepared retinoids are also well known in theart. For example, see U.S. Pat. No. 5,234,926 which is incorporated hereby reference thereto in its entirety which discloses methods ofsynthesizing disubstituted acetylenes bearing heteroaeromatic andheterobicyclic groups with a selective activity as RAR agonists. U.S.Pat. No. 4,326,055 is incorporated herewith by reference thereto in itsentirety for disclosing methods for synthesizing 5,6,7,8-tetrahydronaphthal and indanyl stilbene derivatives with retinoid-like activity.

[0065] Examples of synthetic agonists suitable for use in the practiceof this invention are ethyl6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate (Compound 168) and6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid (Compound 299),whose synthesis is disclosed in U.S. Pat. No. 5,234,926 as Examples 6and 24, respectively; andp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoicacid (Compound 183), whose synthesis is disclosed in U.S. Pat. No.4,326,055, and2-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthaleen-2-yl)propen-1-yl]thiophene-4-carboxylicacid (Compound 701), whose synthesis is disclosed in U.S. Pat. No.5,324,840, Example 11.

[0066] Alternatively, the sclera plug 10, while being generallyhomogeneous, may include a film 50 of retinoid thereon in order toimprove biocompatibility in a manner similar to the improvedbiocompatibility of a non-bioerodible device 42 such as shown in FIG. 3.

[0067] Accompanying the hereinabove described devices is a method inaccordance with the present invention for improving the biocompatibilityof an implant in tissue which includes the step of providing atherapeutic agent, providing a carrier sized for insertion into thetissue in which the release of a therapeutic agent is desired,incorporating the therapeutic agent into a carrier in a manner enablingthe time released of the therapeutic agent and incorporating theretinoid into the carrier in an amount effective for improving thebiocompatibility of a carrier in the tissue. This method, of course,corresponds to the device 10 shown in FIGS. 1 and 2.

[0068] Correspondingly, a method in accordance with the presentinvention relating to the device 42 shown in FIG. 3 include combiningthe retinoid 40 with the prosthesis 42. This method may include thedeposition of a film 40 on the prosthesis 42 or imbedding the retinoidinto surface 44 of the prosthesis.

[0069] All of the hereinabove recited retinoids may be used inaccordance with the method of the present invention.

[0070] The following example illustrates the effectiveness of the methodand devices of the present invention. It should be appreciated that theexample is set forth herein for the purpose of illustration only and isnot to be regarded as limiting to any of the specific materials ormethods disclosed.

EXAMPLE 1

[0071] An implantable device 10 was prepared as follows:

[0072] Retinal plugs were manufactured from poly(D,L)lactic acid (PLA)with an intrinsic viscosity of 0.6 DL/G. The retinoid 6-[(4;4-dimethylthiochroman-6-yl)ethynl]nicotinic acid (AGN190299) was mixed withpolymer in a three-dimensional mixer. The mixture was then extruded at85° C. into a homogeneous rod. The retinoid was incorporated into thepolymeric plug at a concentration of 10%. The extruded plug was then cutto a length of 3.0 mm and had a diameter of 1.5 mm. A 0.5 mm hole wasdrilled into the distal end of the plug to allow for suture fixation tothe sclera. Placebo plugs containing no retinoid were also manufacturedto the same dimensions. The average weight of the plugs was 8 mg. Allplugs were sterilized by gamma irradiation at 1 Mrad.

[0073] The plugs were then implanted into pigmented rabbits as shown inFIG. 2. The rabbit eyes were vitrectomized and the retinal plugs with orwithout incorporated retinoid were inserted through a sclerotomy 3 mmposterior to the corneoscleral limbus. The plugs were then fixated withthe suture used to close the sclerotomy. An intravitreal injection of500,000 human RPE cells was given to simulate traction retinaldetachment. The rabbits were sacrificed at 28 days and histopathologywas done.

[0074] These observed results are shown in FIG. 7 for the placebo plugand in FIG. 8 for the plug 10 including the retinoid as hereinabovedescribed.

[0075]FIG. 7 is a drawing showing the encapsulation of a placebo plug 28days after insertion into the vitreous through the sclera. The plug iscomprised of polylactic acid. The plug disappears during the processingof the eye (A). The tissues surrounding the plug were stained with PASand show a fibrous capsule surrounding the area (B) where the placebowas previously located. The capsule that surrounded the polylactic acidplug shows a very prominent inflammatory response with inflammatory cellinfiltration (C).

[0076]FIG. 8 is a drawing showing the encapsulation of a retinoidcontaining plug 28 days after insertion. The polylactic acid plugcontain 10% by weight of the retinoid 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinic acid (AGN190299). The plug disappearsin the processing of the eye (A). The tissues surrounding the retinoidcontaining plug were stained with PAS. The figure shows that the capsulesurrounding the AGN190299 plug (B) has very little fibrous inflammation(C).

[0077] Although there has been hereinabove described a particulararrangement of implantable devices and methods in accordance with thepresent invention, for the purpose of illustrating the manner in whichthe invention may be used to advantage, it should be appreciated thatthe invention is not limited thereto. Accordingly, any and allmodifications, variations or equivalent arrangements which may occur tothose skilled in the art, should be considered to be within the scope ofthe present invention as defined in the appended claims.

What is claimed is:
 1. An implantable device for providing systemic orlocal release of a therapeutic agent in tissue, the device comprising: atherapeutic agent; an implant sized for insertion into tissue in whichsystemic release of the therapeutic agent is desired, said implantincluding means for providing controlled release of the therapeuticagent; and retinoid means, present in said implant, for improvingbiocompatibility of said device in said tissue.
 2. The device accordingto claim 1 wherein said retinoid means comprises a retinoid receptoragonist.
 3. The device according to claim 2 wherein said therapeuticagent, carrier and retinoid means are homogeneous.
 4. The deviceaccording to claim 3 wherein said means for providing controlled releaseof the therapeutic agent comprises a biodegradable polymer.
 5. Thedevice according to claim 4 wherein said biodegradable polymer comprisesa poly(lactic acid).
 6. The device according to claim 4 wherein saidbiodegradable polymer comprises poly(lactide-co-glycolide).
 7. Thedevice according to claim 2 wherein said retinoid receptor agonistcomprises a naturally occurring retinoid.
 8. The device according toclaim 2 wherein said retinoid receptor agonist is selected from a groupconsisting of Vitamin A (retinal), Vitamin A aldehyde (retinal), VitaminA acid (retinoic acid) and their synthetic and natural congeners.
 9. Thedevice according to claim 2 wherein the retinoid receptor agonistcomprises ethy-6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate.10. The device according to claim 2 wherein the retinoid receptoragonist comprises 6-[2-(4,4-dimethylchroman6-yl)ethynyl]nicotinic acid.11. The device according to claim 2 wherein the retinoid receptoragonist comprisesp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)propenyl]-benzoicacid.
 12. An implantable device for providing systemic or local releaseof a therapeutic agent in tissue, the device comprising: an implantsized for insertion into tissue in which systemic or local release of atherapeutic agent is desired, said implant including means for providingcontrolled release of the therapeutic agent; and retinoid means, presentin said implant as the therapeutic agent, for improving biocompatibilityof said device in said tissue.
 13. The device according to claim 13wherein said retinoid means comprises a retinoid receptor agonist. 14.The device according to claim 13 wherein said carrier and retinoid meansare homogeneous.
 15. The device according to claim 14 wherein said meansfor providing controlled release for the therapeutic agent comprises abiodegradable polymer.
 16. The device according to claim 15 wherein saidbiodegradable polymer comprises a poly(lactic acid).
 17. The deviceaccording to claim 15 wherein said biodegradable polymer comprises apoly(lactide-co-glycolide).
 18. The device according to claim 16 whereinsaid retinoid receptor comprises a naturally occurring retinoid.
 19. Animplantable device comprising; a surgically implantable prosthesis; and,in combination therewith, retinoid means for improving biocompatibilityof the prosthesis.
 20. The device according to claim 19 wherein saidretinoid means is present in the form of a film on the prosthesis. 21.The device according to claim 20 wherein said retinoid means is bondedto a surface of the prostheses.
 22. The device according to claim 19wherein said retinoid means comprises a naturally occurring treinoid.23. The device according to claim 19 wherein said retinoid means isselected from a group consisting of Vitamin A (retinol), Vitamin Aaldehyde (retinal), Vitamin A acid (retinoic acid) and their syntheticand natural congeners.
 24. A device according to claim 24 wherein theretinoid comprisesp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyll-2-naphthyl)propenyl]-benzoicacid.